The Synthesis of Propofol and Similar Analogs

The use of anesthetics can be traced back to Ancient Sumeria and have been written about in the texts of civilizations such as the Greeks and Romans. However, it wasn't until the 19th Century that General Anesthesia came into fruition. The first recorded use was at Massachusetts General Hospital in 1846. Dr. John Collins Warren used diethyl ether, commonly known as ether, as an inhalation anesthetic. Unfortunately, ether was complicated by its slow effects and unpleasant recovery period.

The next development in General Anesthesia did not occur until the 20th Century. Intravenous anesthetics had been widely avoided because they caused complications involving the obstruction of the airway. However, these complications were greatly minimized with the invention of the laryngoscope in 1913 by Chavalier Jackson.

In 1934, Sodium pentothal (also known as Thiopental sodium) was synthesized by Ernest Volwimer and Donalee Tabern of Abbott Laboratories and was administered intravenously by Ralph Waters on March 8, 1934. Unlike it's predecessors, Sodium pentothal caused almost immediate loss of consciousness and had a much shorter recovery period. However, it's major drawback was dosage. Ironically, the effective dose was 75% of the lethal dose.

 Today, the most commonly used intravenous anesthetic is Diprivan (better known as Propofol) because it can be administered quickly and effectively and has a very large margin of safety. In fact, the demand for Propofol throughout the medical community has been so great that suppliers such as Hospira, Teva, AstraZeneca have not been able to keep up. As a result, in recent months the FDA has been forced to approve and import similar drugs such as Propoven (See article here).

In recent news, pharmaceutical companies have been developing similar analogs of Propofol to help resolve national shortages. One such company is Abraxis BioScience, which is a subsidiary of Celgene Coporation (The patent and publication from Celgene can be found here.)

As outlined in their patent, the current method of producing these analogs is by treating a mixture of 2,6-dialkyl phenol with acyl chloride in the presence of aluminum chloride for 24 hours:

This mechanism  is known as Friedel-Crafts Acylation and proceeds as follows:

 Sources:

1. http://www.webmd.com/pain-management/features/propofol-faq
2. http://en.wikipedia.org/wiki/History_of_general_anesthesia#20th_century